{"gene":"METTL13","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2018,"finding":"METTL13 contains two distinct methyltransferase domains: an N-terminal domain that methylates the N-terminus of eEF1A, and a second domain that methylates Lys55 (K55) of eEF1A. Biochemical and structural analyses provided detailed mechanistic insights into recognition of the eEF1A N-terminus by METTL13. Ribosome profiling showed that loss of METTL13 function alters translation dynamics and changes translation rates of specific codons.","method":"Biochemical methyltransferase assays, structural analysis, ribosome profiling, wide range of experimental approaches","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assays, structural analysis, and ribosome profiling (multiple orthogonal methods) in a single rigorous study","pmids":["30143613"],"is_preprint":false},{"year":2019,"finding":"METTL13 catalyzes dimethylation of eEF1A at lysine 55 (eEF1AK55me2), which increases eEF1A's intrinsic GTPase activity in vitro and increases protein production in cells. This methylation is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo.","method":"In vitro GTPase activity assay, cell-based protein synthesis assays, mouse tumor models, patient-derived xenografts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay demonstrating GTPase activation, combined with cell-based and in vivo tumor models; independently consistent with PMID:30143613","pmids":["30612740"],"is_preprint":false},{"year":2018,"finding":"A dominant substitution (p.Arg544Gln) in METTL13 is the DFNM1 suppressor of GAB1-associated (DFNB26) deafness. METTL13 co-immunoprecipitates with GAB1 and SPRY2 in mouse auditory sensory neurons, indicating formation of at least a tripartite complex. METTL13 modification of MET/HGF signaling is implicated as the suppression mechanism, with SPRY2 dysregulation rescued by the modifier allele.","method":"Co-immunoprecipitation, zebrafish morphant rescue with human METTL13 mRNA, mouse co-localization studies, lymphoblastoid cell gene expression analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and in vivo rescue in zebrafish, single lab with two orthogonal methods","pmids":["29408807"],"is_preprint":false},{"year":2023,"finding":"METTL13 inhibits METTL11A (NRMT1/NTMT1) Nα-trimethylase activity through a direct regulatory interaction, independently of METTL13 catalytic activity. Conversely, METTL11A promotes METTL13's K55 methylation activity but inhibits its Nα-methylation activity. METTL11A, METTL11B, and METTL13 can form a tripartite complex, in which METTL13's inhibitory effects on METTL11A take precedence over METTL11B's activating effects.","method":"Co-immunoprecipitation, mass spectrometry, in vitro methylation assays, catalytic mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation assays with catalytic mutants plus co-IP and MS; multiple orthogonal methods in single rigorous study","pmids":["36889590"],"is_preprint":false},{"year":2023,"finding":"Mettl13 induces lysine methylation of c-Cbl, impairing c-Cbl stability and thereby inhibiting c-Cbl-mediated ubiquitination and degradation of SERCA2a. This stabilization of SERCA2a maintains Ca2+ transient amplitude and cardiac contractile function in cardiomyocytes.","method":"AAV9-mediated cardiomyocyte-specific overexpression, siRNA knockdown, Ca2+ transient imaging, western blotting for SERCA2a and ubiquitination, mouse MI model","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiments and protein ubiquitination assays in vivo and in vitro; single lab with multiple approaches","pmids":["37450238"],"is_preprint":false},{"year":2023,"finding":"The C. elegans METTL13 ortholog (METL-13) methylates eEF1A (EEF-1A) at the same N-terminal and K55 positions as the human protein, as confirmed by methyltransferase assays and mass spectrometry. The tumor-promoting role of METL-13 depends on methylation of EEF-1A and is conserved in C. elegans, while METL-13 is dispensable for normal animal growth, development, and stress responses.","method":"Methyltransferase assays, mass spectrometry, C. elegans genetic knockout models","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methyltransferase assay with MS confirmation plus in vivo genetic models; multiple orthogonal methods","pmids":["37347777"],"is_preprint":false},{"year":2025,"finding":"AGD1 binds METTL13 and USP10, forming a complex in which USP10-mediated deubiquitination stabilizes METTL13 protein. METTL13 in this complex controls mRNA decay of CD44 via m6A methylation, activating the pSTAT3/PI3K-AKT signaling pathway to promote cancer stem cell stemness and docetaxel resistance in castration-resistant prostate cancer.","method":"RNA pull-down, mass spectrometry, co-immunoprecipitation, RIP assay, MeRIP assay, SELECT assay, xenograft and organoid models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (co-IP, MeRIP, SELECT) in single lab; mechanistic pathway established but m6A writer role for METTL13 is novel and not yet independently replicated","pmids":["39806412"],"is_preprint":false},{"year":2021,"finding":"METTL13 co-immunoprecipitates with c-Myc in ccRCC cells and negatively regulates c-Myc protein expression, as well as suppressing the PI3K/AKT/mTOR/HIF-1α pathway.","method":"Co-immunoprecipitation, western blotting, WGCNA bioinformatics, functional knockdown/overexpression","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP with limited mechanistic follow-up; single lab, single method for the interaction claim","pmids":["33985542"],"is_preprint":false},{"year":2021,"finding":"METTL13 intracellular localization was determined to include the cytoplasm, mitochondria, and nucleus by immunogold electron microscopy.","method":"Immunogold electron microscopy","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization method, reported in PMID:27659353 (2016), single lab without functional consequence linked","pmids":["27659353"],"is_preprint":false},{"year":2018,"finding":"FEAT (METTL13) knockdown in MA-10 Leydig cells increases primary cilia formation with enhanced AMPK activation, and diminishes INSL3 expression. Heterozygous Mettl13+/- male mice develop bilateral intraabdominal cryptorchidism with markedly decreased INSL3 in Leydig cells, establishing that METTL13 facilitates INSL3 production essential for transabdominal testis migration.","method":"siRNA knockdown, immunofluorescence, immunohistochemistry in Mettl13+/- mice","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model plus cell-based knockdown with defined phenotypic readout; multiple methods in single lab","pmids":["30178547"],"is_preprint":false},{"year":2016,"finding":"METTL13 negatively regulates cell proliferation in bladder cancer by reinstating the G1/S checkpoint via coordinated downregulation of CDK6, CDK4, and CCND1 and decreased Rb phosphorylation. METTL13 also inhibits cell migration and invasion through downregulation of FAK phosphorylation, AKT phosphorylation, β-catenin expression, and MMP-9 expression.","method":"Overexpression/knockdown in cancer cell lines, western blotting, cell cycle analysis, migration/invasion assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional phenotype with pathway markers by western blot; single lab, no direct substrate/interaction validation","pmids":["26763933"],"is_preprint":false},{"year":2025,"finding":"A bisubstrate inhibitor probe (NT32) targeting METTL13 occupies both the SAM/SAH-binding pocket and the peptide substrate-binding site simultaneously (bivalent binding mode), as revealed by molecular docking and MD simulations. NT32 specifically stabilized METTL13 protein in a cellular thermal shift assay.","method":"Molecular docking, molecular dynamics simulation, cellular thermal shift assay","journal":"Bioorganic chemistry","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational with only one in-cell biophysical assay (CETSA); no in vitro enzymatic inhibition or structural data in the abstract","pmids":["41468753"],"is_preprint":false},{"year":2022,"finding":"METTL13 regulates HN1L expression in gastric cancer cells, and eEF1A is involved in this regulation in a K55 methylation-independent manner. A positive feedback circuit exists: METTL13 promotes HN1L expression, and HN1L in turn facilitates METTL13 expression.","method":"siRNA knockdown, overexpression, western blotting, in vivo tumor models","journal":"Journal of cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional knockdown/overexpression with pathway markers; K55-independence claim based on cell-level readouts, single lab","pmids":["35925508"],"is_preprint":false},{"year":2026,"finding":"METTL13 regulates esophageal squamous cell carcinoma progression by enhancing SAA1 expression at the translational level (not transcriptional), as determined by polyribosome-bound mRNA sequencing, leading to altered lipid metabolism and cancer stem cell properties.","method":"Polyribosome-bound mRNA sequencing, qRT-PCR, western blot, seahorse metabolic assay, in vivo mouse models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome-associated mRNA sequencing distinguishes translational from transcriptional regulation; multiple orthogonal methods in single lab","pmids":["41764490"],"is_preprint":false}],"current_model":"METTL13 is a dual protein methyltransferase with two distinct catalytic domains: an N-terminal methyltransferase domain that tri-methylates the α-amino group of eEF1A, and a lysine methyltransferase domain that dimethylates eEF1A at Lys55; together these modifications increase eEF1A's GTPase activity and global translational output, modulate codon-specific translation rates, and drive Ras-dependent tumorigenesis, while METTL13 also methylates c-Cbl to stabilize SERCA2a in cardiomyocytes, participates in a regulatory complex with METTL11A/11B that bidirectionally controls Nα-methylation activity, and physically interacts with GAB1/SPRY2 to modulate MET/HGF signaling in the inner ear."},"narrative":{"mechanistic_narrative":"METTL13 is a dual-domain protein methyltransferase that post-translationally modifies the translation elongation factor eEF1A to control global and codon-specific translation [PMID:30143613]. Its N-terminal domain tri-methylates the eEF1A N-terminus while a second lysine methyltransferase domain dimethylates eEF1A at Lys55, and structural and ribosome-profiling analyses establish that these modifications reshape translation dynamics [PMID:30143613]. eEF1A-K55 dimethylation increases the intrinsic GTPase activity of eEF1A and raises protein output, an activity co-opted by Ras-driven cancers to elevate translation and promote tumorigenesis in vivo [PMID:30612740]; this eEF1A-targeting role and its tumor-promoting dependence on eEF1A methylation are conserved in the C. elegans ortholog [PMID:37347777]. METTL13 catalytic output is itself regulated through a tripartite complex with the Nα-trimethyltransferases METTL11A and METTL11B, in which METTL13 directly inhibits METTL11A activity while METTL11A reciprocally promotes K55 methylation but represses Nα-methylation by METTL13 [PMID:36889590]. Beyond eEF1A, METTL13 methylates c-Cbl to block c-Cbl-mediated ubiquitination and degradation of SERCA2a, thereby preserving Ca2+ transients and contractile function in cardiomyocytes [PMID:37450238]. A dominant METTL13 substitution acts as the DFNM1 suppressor of GAB1-associated DFNB26 deafness, where METTL13 co-immunoprecipitates with GAB1 and SPRY2 and modifies MET/HGF signaling [PMID:29408807]. Across multiple cancers METTL13 influences proliferation and translational output [PMID:30178547, PMID:41764490], but the molecular basis of several of these context-specific roles is not resolved in the available corpus.","teleology":[{"year":2018,"claim":"Establishing what METTL13 does molecularly: it is a bifunctional methyltransferase with two domains targeting distinct sites on eEF1A, linking the enzyme directly to translational control.","evidence":"Biochemical methyltransferase assays, structural analysis, and ribosome profiling in cells","pmids":["30143613"],"confidence":"High","gaps":["Did not establish the functional consequence of each individual methyl mark for GTPase activity","Codon-specific translation effects not connected to downstream phenotypes"]},{"year":2018,"claim":"Connecting METTL13 to human disease and to a non-eEF1A interaction context, showing it forms a complex with GAB1/SPRY2 and modifies MET/HGF signaling as a genetic suppressor of deafness.","evidence":"Co-immunoprecipitation, zebrafish morphant rescue with human METTL13 mRNA, and mouse co-localization in auditory neurons","pmids":["29408807"],"confidence":"Medium","gaps":["Whether suppression depends on METTL13 catalytic activity not resolved","Direct substrate within the GAB1/SPRY2/MET axis not identified"]},{"year":2018,"claim":"Linking METTL13 to a developmental phenotype: it facilitates INSL3 production required for transabdominal testis migration.","evidence":"siRNA knockdown in MA-10 Leydig cells and Mettl13+/- mouse cryptorchidism phenotyping","pmids":["30178547"],"confidence":"Medium","gaps":["Molecular substrate connecting METTL13 to INSL3/AMPK/cilia not identified","Whether the effect requires methyltransferase activity unknown"]},{"year":2019,"claim":"Defining the functional payoff of K55 dimethylation: it activates eEF1A GTPase activity and boosts translation, a mechanism Ras-driven tumors exploit.","evidence":"In vitro GTPase assays, cell-based protein synthesis assays, and mouse tumor and patient-derived xenograft models","pmids":["30612740"],"confidence":"High","gaps":["How the N-terminal trimethylation contributes alongside K55me2 not fully separated","Mechanism coupling increased GTPase activity to oncogenic selectivity unresolved"]},{"year":2023,"claim":"Showing METTL13 activity is itself regulated by a methyltransferase complex, with reciprocal modulation of Nα- versus K55 methylation by METTL11A/11B.","evidence":"Co-IP, mass spectrometry, and in vitro methylation assays with catalytic mutants","pmids":["36889590"],"confidence":"High","gaps":["Structural basis of the tripartite complex not determined","Physiological conditions selecting between Nα- and K55 methylation outputs unknown"]},{"year":2023,"claim":"Extending METTL13 substrate scope beyond eEF1A: methylation of c-Cbl stabilizes SERCA2a to maintain cardiomyocyte Ca2+ handling.","evidence":"AAV9 cardiomyocyte overexpression, siRNA knockdown, Ca2+ imaging, ubiquitination assays, and mouse MI model","pmids":["37450238"],"confidence":"Medium","gaps":["c-Cbl methylation site not mapped","Whether c-Cbl is a direct METTL13 substrate not shown by reconstitution"]},{"year":2023,"claim":"Demonstrating evolutionary conservation of the eEF1A-methylation and tumor-promoting functions in an invertebrate ortholog while showing dispensability for normal development.","evidence":"Methyltransferase assays, mass spectrometry, and C. elegans genetic knockout models","pmids":["37347777"],"confidence":"High","gaps":["Conservation of the c-Cbl/SERCA2a and complex-regulation functions not tested"]},{"year":2025,"claim":"Probing whether METTL13 can act as an m6A writer, proposing CD44 mRNA decay control driving stemness and drug resistance via a USP10-stabilized complex.","evidence":"RNA pull-down, MS, co-IP, RIP, MeRIP, SELECT, and xenograft/organoid models","pmids":["39806412"],"confidence":"Medium","gaps":["m6A writer activity for METTL13 is novel and not independently replicated","Direct catalytic deposition of m6A not demonstrated in vitro"]},{"year":2025,"claim":"Developing a chemical tool: a bisubstrate probe occupying both SAM and peptide pockets that engages METTL13 in cells.","evidence":"Molecular docking, MD simulation, and cellular thermal shift assay","pmids":["41468753"],"confidence":"Low","gaps":["Primarily computational with no in vitro enzymatic inhibition data","No structural confirmation of the bivalent binding mode"]},{"year":2026,"claim":"Showing METTL13 acts at the translational level in cancer, enhancing SAA1 protein production to alter lipid metabolism and stemness.","evidence":"Polyribosome-bound mRNA sequencing, metabolic assays, and in vivo mouse models","pmids":["41764490"],"confidence":"Medium","gaps":["Whether SAA1 translational enhancement is mediated through eEF1A methylation not established","Direct molecular link from METTL13 to SAA1 mRNA not defined"]},{"year":null,"claim":"Whether METTL13's many context-specific roles (deafness modification, cardiac SERCA2a stabilization, m6A-dependent mRNA decay, codon-specific cancer translation) all derive from its eEF1A methyltransferase activity or reflect independent substrate/complex functions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying biochemical test separating catalytic from scaffolding roles across tissues","Substrate sites for non-eEF1A targets largely unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["METTL11A/METTL11B/METTL13 tripartite complex","GAB1/SPRY2/METTL13 complex","AGD1/USP10/METTL13 complex"],"partners":["EEF1A1","METTL11A","METTL11B","GAB1","SPRY2","CBL","USP10","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6R0","full_name":"eEF1A lysine and N-terminal methyltransferase","aliases":["Methyltransferase-like protein 13"],"length_aa":699,"mass_kda":78.8,"function":"Dual methyltransferase that catalyzes methylation of elongation factor 1-alpha (EEF1A1 and EEF1A2) at two different positions, and is therefore involved in the regulation of mRNA translation (PubMed:30143613, PubMed:30612740). Via its C-terminus, methylates EEF1A1 and EEF1A2 at the N-terminal residue 'Gly-2' (PubMed:30143613). Via its N-terminus dimethylates EEF1A1 and EEF1A2 at residue 'Lys-55' (PubMed:30143613, PubMed:30612740). Has no activity towards core histones H2A, H2B, H3 and H4 (PubMed:30612740)","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q8N6R0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/METTL13","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/METTL13","total_profiled":1310},"omim":[{"mim_id":"617987","title":"METHYLTRANSFERASE 13, EEF1A LYSINE AND N-TERMINAL METHYLTRANSFERASE; METTL13","url":"https://www.omim.org/entry/617987"},{"mim_id":"605429","title":"DEAFNESS, AUTOSOMAL RECESSIVE 26, MODIFIER OF; DFNB26M","url":"https://www.omim.org/entry/605429"},{"mim_id":"605428","title":"DEAFNESS, AUTOSOMAL RECESSIVE 26; DFNB26","url":"https://www.omim.org/entry/605428"},{"mim_id":"604439","title":"GRB2-ASSOCIATED BINDING PROTEIN 1; GAB1","url":"https://www.omim.org/entry/604439"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/METTL13"},"hgnc":{"alias_symbol":["CGI-01","FEAT"],"prev_symbol":["KIAA0859","DFNM1","EEF1AKNMT"]},"alphafold":{"accession":"Q8N6R0","domains":[{"cath_id":"3.40.50.150","chopping":"33-256","consensus_level":"medium","plddt":90.8243,"start":33,"end":256},{"cath_id":"-","chopping":"262-374","consensus_level":"high","plddt":86.5705,"start":262,"end":374},{"cath_id":"3.40.50.150","chopping":"471-697","consensus_level":"high","plddt":91.0141,"start":471,"end":697},{"cath_id":"2.40.50","chopping":"383-428","consensus_level":"medium","plddt":90.2789,"start":383,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6R0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6R0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6R0-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=METTL13","jax_strain_url":"https://www.jax.org/strain/search?query=METTL13"},"sequence":{"accession":"Q8N6R0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6R0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6R0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6R0"}},"corpus_meta":[{"pmid":"30612740","id":"PMC_30612740","title":"METTL13 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distinct methyltransferase domains: an N-terminal domain that methylates the N-terminus of eEF1A, and a second domain that methylates Lys55 (K55) of eEF1A. Biochemical and structural analyses provided detailed mechanistic insights into recognition of the eEF1A N-terminus by METTL13. Ribosome profiling showed that loss of METTL13 function alters translation dynamics and changes translation rates of specific codons.\",\n      \"method\": \"Biochemical methyltransferase assays, structural analysis, ribosome profiling, wide range of experimental approaches\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assays, structural analysis, and ribosome profiling (multiple orthogonal methods) in a single rigorous study\",\n      \"pmids\": [\"30143613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL13 catalyzes dimethylation of eEF1A at lysine 55 (eEF1AK55me2), which increases eEF1A's intrinsic GTPase activity in vitro and increases protein production in cells. This methylation is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo.\",\n      \"method\": \"In vitro GTPase activity assay, cell-based protein synthesis assays, mouse tumor models, patient-derived xenografts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay demonstrating GTPase activation, combined with cell-based and in vivo tumor models; independently consistent with PMID:30143613\",\n      \"pmids\": [\"30612740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A dominant substitution (p.Arg544Gln) in METTL13 is the DFNM1 suppressor of GAB1-associated (DFNB26) deafness. METTL13 co-immunoprecipitates with GAB1 and SPRY2 in mouse auditory sensory neurons, indicating formation of at least a tripartite complex. METTL13 modification of MET/HGF signaling is implicated as the suppression mechanism, with SPRY2 dysregulation rescued by the modifier allele.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish morphant rescue with human METTL13 mRNA, mouse co-localization studies, lymphoblastoid cell gene expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and in vivo rescue in zebrafish, single lab with two orthogonal methods\",\n      \"pmids\": [\"29408807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL13 inhibits METTL11A (NRMT1/NTMT1) Nα-trimethylase activity through a direct regulatory interaction, independently of METTL13 catalytic activity. Conversely, METTL11A promotes METTL13's K55 methylation activity but inhibits its Nα-methylation activity. METTL11A, METTL11B, and METTL13 can form a tripartite complex, in which METTL13's inhibitory effects on METTL11A take precedence over METTL11B's activating effects.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, in vitro methylation assays, catalytic mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation assays with catalytic mutants plus co-IP and MS; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36889590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mettl13 induces lysine methylation of c-Cbl, impairing c-Cbl stability and thereby inhibiting c-Cbl-mediated ubiquitination and degradation of SERCA2a. This stabilization of SERCA2a maintains Ca2+ transient amplitude and cardiac contractile function in cardiomyocytes.\",\n      \"method\": \"AAV9-mediated cardiomyocyte-specific overexpression, siRNA knockdown, Ca2+ transient imaging, western blotting for SERCA2a and ubiquitination, mouse MI model\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiments and protein ubiquitination assays in vivo and in vitro; single lab with multiple approaches\",\n      \"pmids\": [\"37450238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The C. elegans METTL13 ortholog (METL-13) methylates eEF1A (EEF-1A) at the same N-terminal and K55 positions as the human protein, as confirmed by methyltransferase assays and mass spectrometry. The tumor-promoting role of METL-13 depends on methylation of EEF-1A and is conserved in C. elegans, while METL-13 is dispensable for normal animal growth, development, and stress responses.\",\n      \"method\": \"Methyltransferase assays, mass spectrometry, C. elegans genetic knockout models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methyltransferase assay with MS confirmation plus in vivo genetic models; multiple orthogonal methods\",\n      \"pmids\": [\"37347777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AGD1 binds METTL13 and USP10, forming a complex in which USP10-mediated deubiquitination stabilizes METTL13 protein. METTL13 in this complex controls mRNA decay of CD44 via m6A methylation, activating the pSTAT3/PI3K-AKT signaling pathway to promote cancer stem cell stemness and docetaxel resistance in castration-resistant prostate cancer.\",\n      \"method\": \"RNA pull-down, mass spectrometry, co-immunoprecipitation, RIP assay, MeRIP assay, SELECT assay, xenograft and organoid models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (co-IP, MeRIP, SELECT) in single lab; mechanistic pathway established but m6A writer role for METTL13 is novel and not yet independently replicated\",\n      \"pmids\": [\"39806412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL13 co-immunoprecipitates with c-Myc in ccRCC cells and negatively regulates c-Myc protein expression, as well as suppressing the PI3K/AKT/mTOR/HIF-1α pathway.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, WGCNA bioinformatics, functional knockdown/overexpression\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP with limited mechanistic follow-up; single lab, single method for the interaction claim\",\n      \"pmids\": [\"33985542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL13 intracellular localization was determined to include the cytoplasm, mitochondria, and nucleus by immunogold electron microscopy.\",\n      \"method\": \"Immunogold electron microscopy\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization method, reported in PMID:27659353 (2016), single lab without functional consequence linked\",\n      \"pmids\": [\"27659353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FEAT (METTL13) knockdown in MA-10 Leydig cells increases primary cilia formation with enhanced AMPK activation, and diminishes INSL3 expression. Heterozygous Mettl13+/- male mice develop bilateral intraabdominal cryptorchidism with markedly decreased INSL3 in Leydig cells, establishing that METTL13 facilitates INSL3 production essential for transabdominal testis migration.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, immunohistochemistry in Mettl13+/- mice\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model plus cell-based knockdown with defined phenotypic readout; multiple methods in single lab\",\n      \"pmids\": [\"30178547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"METTL13 negatively regulates cell proliferation in bladder cancer by reinstating the G1/S checkpoint via coordinated downregulation of CDK6, CDK4, and CCND1 and decreased Rb phosphorylation. METTL13 also inhibits cell migration and invasion through downregulation of FAK phosphorylation, AKT phosphorylation, β-catenin expression, and MMP-9 expression.\",\n      \"method\": \"Overexpression/knockdown in cancer cell lines, western blotting, cell cycle analysis, migration/invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional phenotype with pathway markers by western blot; single lab, no direct substrate/interaction validation\",\n      \"pmids\": [\"26763933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A bisubstrate inhibitor probe (NT32) targeting METTL13 occupies both the SAM/SAH-binding pocket and the peptide substrate-binding site simultaneously (bivalent binding mode), as revealed by molecular docking and MD simulations. NT32 specifically stabilized METTL13 protein in a cellular thermal shift assay.\",\n      \"method\": \"Molecular docking, molecular dynamics simulation, cellular thermal shift assay\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational with only one in-cell biophysical assay (CETSA); no in vitro enzymatic inhibition or structural data in the abstract\",\n      \"pmids\": [\"41468753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL13 regulates HN1L expression in gastric cancer cells, and eEF1A is involved in this regulation in a K55 methylation-independent manner. A positive feedback circuit exists: METTL13 promotes HN1L expression, and HN1L in turn facilitates METTL13 expression.\",\n      \"method\": \"siRNA knockdown, overexpression, western blotting, in vivo tumor models\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional knockdown/overexpression with pathway markers; K55-independence claim based on cell-level readouts, single lab\",\n      \"pmids\": [\"35925508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL13 regulates esophageal squamous cell carcinoma progression by enhancing SAA1 expression at the translational level (not transcriptional), as determined by polyribosome-bound mRNA sequencing, leading to altered lipid metabolism and cancer stem cell properties.\",\n      \"method\": \"Polyribosome-bound mRNA sequencing, qRT-PCR, western blot, seahorse metabolic assay, in vivo mouse models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome-associated mRNA sequencing distinguishes translational from transcriptional regulation; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"41764490\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"METTL13 is a dual protein methyltransferase with two distinct catalytic domains: an N-terminal methyltransferase domain that tri-methylates the α-amino group of eEF1A, and a lysine methyltransferase domain that dimethylates eEF1A at Lys55; together these modifications increase eEF1A's GTPase activity and global translational output, modulate codon-specific translation rates, and drive Ras-dependent tumorigenesis, while METTL13 also methylates c-Cbl to stabilize SERCA2a in cardiomyocytes, participates in a regulatory complex with METTL11A/11B that bidirectionally controls Nα-methylation activity, and physically interacts with GAB1/SPRY2 to modulate MET/HGF signaling in the inner ear.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"METTL13 is a dual-domain protein methyltransferase that post-translationally modifies the translation elongation factor eEF1A to control global and codon-specific translation [#0]. Its N-terminal domain tri-methylates the eEF1A N-terminus while a second lysine methyltransferase domain dimethylates eEF1A at Lys55, and structural and ribosome-profiling analyses establish that these modifications reshape translation dynamics [#0]. eEF1A-K55 dimethylation increases the intrinsic GTPase activity of eEF1A and raises protein output, an activity co-opted by Ras-driven cancers to elevate translation and promote tumorigenesis in vivo [#1]; this eEF1A-targeting role and its tumor-promoting dependence on eEF1A methylation are conserved in the C. elegans ortholog [#5]. METTL13 catalytic output is itself regulated through a tripartite complex with the Nα-trimethyltransferases METTL11A and METTL11B, in which METTL13 directly inhibits METTL11A activity while METTL11A reciprocally promotes K55 methylation but represses Nα-methylation by METTL13 [#3]. Beyond eEF1A, METTL13 methylates c-Cbl to block c-Cbl-mediated ubiquitination and degradation of SERCA2a, thereby preserving Ca2+ transients and contractile function in cardiomyocytes [#4]. A dominant METTL13 substitution acts as the DFNM1 suppressor of GAB1-associated DFNB26 deafness, where METTL13 co-immunoprecipitates with GAB1 and SPRY2 and modifies MET/HGF signaling [#2]. Across multiple cancers METTL13 influences proliferation and translational output [#9, #13], but the molecular basis of several of these context-specific roles is not resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing what METTL13 does molecularly: it is a bifunctional methyltransferase with two domains targeting distinct sites on eEF1A, linking the enzyme directly to translational control.\",\n      \"evidence\": \"Biochemical methyltransferase assays, structural analysis, and ribosome profiling in cells\",\n      \"pmids\": [\"30143613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the functional consequence of each individual methyl mark for GTPase activity\", \"Codon-specific translation effects not connected to downstream phenotypes\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connecting METTL13 to human disease and to a non-eEF1A interaction context, showing it forms a complex with GAB1/SPRY2 and modifies MET/HGF signaling as a genetic suppressor of deafness.\",\n      \"evidence\": \"Co-immunoprecipitation, zebrafish morphant rescue with human METTL13 mRNA, and mouse co-localization in auditory neurons\",\n      \"pmids\": [\"29408807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether suppression depends on METTL13 catalytic activity not resolved\", \"Direct substrate within the GAB1/SPRY2/MET axis not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking METTL13 to a developmental phenotype: it facilitates INSL3 production required for transabdominal testis migration.\",\n      \"evidence\": \"siRNA knockdown in MA-10 Leydig cells and Mettl13+/- mouse cryptorchidism phenotyping\",\n      \"pmids\": [\"30178547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate connecting METTL13 to INSL3/AMPK/cilia not identified\", \"Whether the effect requires methyltransferase activity unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the functional payoff of K55 dimethylation: it activates eEF1A GTPase activity and boosts translation, a mechanism Ras-driven tumors exploit.\",\n      \"evidence\": \"In vitro GTPase assays, cell-based protein synthesis assays, and mouse tumor and patient-derived xenograft models\",\n      \"pmids\": [\"30612740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the N-terminal trimethylation contributes alongside K55me2 not fully separated\", \"Mechanism coupling increased GTPase activity to oncogenic selectivity unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing METTL13 activity is itself regulated by a methyltransferase complex, with reciprocal modulation of Nα- versus K55 methylation by METTL11A/11B.\",\n      \"evidence\": \"Co-IP, mass spectrometry, and in vitro methylation assays with catalytic mutants\",\n      \"pmids\": [\"36889590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the tripartite complex not determined\", \"Physiological conditions selecting between Nα- and K55 methylation outputs unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending METTL13 substrate scope beyond eEF1A: methylation of c-Cbl stabilizes SERCA2a to maintain cardiomyocyte Ca2+ handling.\",\n      \"evidence\": \"AAV9 cardiomyocyte overexpression, siRNA knockdown, Ca2+ imaging, ubiquitination assays, and mouse MI model\",\n      \"pmids\": [\"37450238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"c-Cbl methylation site not mapped\", \"Whether c-Cbl is a direct METTL13 substrate not shown by reconstitution\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating evolutionary conservation of the eEF1A-methylation and tumor-promoting functions in an invertebrate ortholog while showing dispensability for normal development.\",\n      \"evidence\": \"Methyltransferase assays, mass spectrometry, and C. elegans genetic knockout models\",\n      \"pmids\": [\"37347777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the c-Cbl/SERCA2a and complex-regulation functions not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Probing whether METTL13 can act as an m6A writer, proposing CD44 mRNA decay control driving stemness and drug resistance via a USP10-stabilized complex.\",\n      \"evidence\": \"RNA pull-down, MS, co-IP, RIP, MeRIP, SELECT, and xenograft/organoid models\",\n      \"pmids\": [\"39806412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A writer activity for METTL13 is novel and not independently replicated\", \"Direct catalytic deposition of m6A not demonstrated in vitro\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Developing a chemical tool: a bisubstrate probe occupying both SAM and peptide pockets that engages METTL13 in cells.\",\n      \"evidence\": \"Molecular docking, MD simulation, and cellular thermal shift assay\",\n      \"pmids\": [\"41468753\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Primarily computational with no in vitro enzymatic inhibition data\", \"No structural confirmation of the bivalent binding mode\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing METTL13 acts at the translational level in cancer, enhancing SAA1 protein production to alter lipid metabolism and stemness.\",\n      \"evidence\": \"Polyribosome-bound mRNA sequencing, metabolic assays, and in vivo mouse models\",\n      \"pmids\": [\"41764490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SAA1 translational enhancement is mediated through eEF1A methylation not established\", \"Direct molecular link from METTL13 to SAA1 mRNA not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether METTL13's many context-specific roles (deafness modification, cardiac SERCA2a stabilization, m6A-dependent mRNA decay, codon-specific cancer translation) all derive from its eEF1A methyltransferase activity or reflect independent substrate/complex functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical test separating catalytic from scaffolding roles across tissues\", \"Substrate sites for non-eEF1A targets largely unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"METTL11A/METTL11B/METTL13 tripartite complex\",\n      \"GAB1/SPRY2/METTL13 complex\",\n      \"AGD1/USP10/METTL13 complex\"\n    ],\n    \"partners\": [\n      \"EEF1A1\",\n      \"METTL11A\",\n      \"METTL11B\",\n      \"GAB1\",\n      \"SPRY2\",\n      \"CBL\",\n      \"USP10\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}